Erythromycins A through D, represented by Formula I and Table 1 shown below, are well-known and potent anti-bacterial agents, used widely to treat and prevent bacterial infection.
TABLE 1Formula I ErythromycinR1R2A—OH—MeB—H—MeC—OH—HD—H—H
As with other anti-bacterial agents, however, bacterial strains having resistance or insufficient susceptibility to erythromycin have been identified. Also, erythromycin A has only weak activity against Gram-negative bacteria. Therefore, there is a continuing need to identify and synthesize new erythromycin-derived compounds which possess improved anti-bacterial activity, which have lower potential for developed resistance, which possess the desired Gram-negative activity, or which possess unexpected selectivity against target microorganisms.
Generally, 6-O-substituted derivatives of erythromycin are known as anti-bacterial agents. 6-O-Methyl erythromycin A (clarithromycin A, disclosed in U.S. Pat. No. 4,331,803) and 6-O-methyl erythromycin B (clarithromycin B, disclosed in U.S. Pat. No. 4,496,717) are potent macrolide antibiotics.
More recently, 6-O-substituted derivatives of erythromycin having improved antibacterial activities have been disclosed in U.S. Pat. Nos. 5,866,549; 5,872,229; 5,919,916; 5,932,710; 6,040,440; 6,075,011 and 6,124,269 among others.
Among the methods for derivatizing 6-O-allyl erythromycin derivatives is the Heck reaction, with Pd(II) or Pd(0) catalyst, phosphine and inorganic base, as disclosed in U.S. Pat. Nos. 5,866,549 and 6,075,011, and in WO 00/78773.
However, the conventional technique described above has certain disadvantages. For example, in a typical arylation of an allylic erythromycin derivative with a palladium catalyst, a phosphine and an arylating agent, yields are from 30–60%. Moreover, in the references cited above, the reactions required not less than ten mole percent of a palladium catalyst, and were conducted in the presence of an added phosphine ligand. The amount of catalyst required increases the cost of production in terms of added cost of catalyst materials, greater waste to dispose of and potential increase in contaminants to be removed from the final product. Moreover, a shorter reaction time would be advantageous.
Although both phosphine and phosphine-free conditions for Heck reactions are known in the chemical literature, phosphine-free conditions have not been utilized for macrolides such as erythromycin derivatives.
Therefore, methods for more efficient arylation would be advantageous for the construction of a 6-O-substituted side chain, which may increase the overall yield of syntheses of 6-O-substituted erythromycin derivatives. Moreover, it would be advantageous in a multi-step erythromycin derivative synthesis to form an alkene, then to arylate at a much later stage of the overall synthesis.